Dipeptidyl peptidase-4 inhibition by vildagliptin and the effect on insulin secretion and action in response to meal ingestion in type 2 diabetes.
OBJECTIVE
The purpose of this study was to determine the mechanism by which dipeptidyl peptidase-4 inhibitors lower postprandial glucose concentrations.


METHODS
We measured insulin secretion and action as well as glucose effectiveness in 14 subjects with type 2 diabetes who received vildagliptin (50 mg b.i.d.) or placebo for 10 days in random order separated by a 3-week washout. On day 9 of each period, subjects ate a mixed meal. Insulin sensitivity (S(I)), glucose effectiveness, and beta-cell responsivity indexes were estimated using the oral glucose and C-peptide minimal models. At 300 min 0.02 unit/kg insulin was administered intravenously.


RESULTS
Vildagliptin reduced postprandial glucose concentrations (905 +/- 94 vs. 1,008 +/- 104 mmol/6 h, P = 0.02). Vildagliptin did not alter net S(I) (7.71 +/- 1.28 vs. 6.41 +/- 0.84 10(-4) dl x kg(-1) x min(-1) x muU(-1) x ml(-1), P = 0.13) or glucose effectiveness (0.019 +/- 0.002 vs. 0.018 +/- 0.002 dl x kg(-1) x min(-1), P = 0.65). However, the net beta-cell responsivity index was increased (35.7 +/- 5.2 vs. 28.9 +/- 5.2 10(-9) min(-1), P = 0.03) as was total disposition index (381 +/- 48 vs. 261 +/- 35 10(-14) dl x kg(-1) x min(-2) x pmol(-1) x l(-1), P = 0.006). Vildagliptin lowered postprandial glucagon concentrations (27.0 +/- 1.1 vs. 29.7 +/- 1.5 microg x l(-1) x 6 h(-1), P = 0.03), especially after administration of exogenous insulin (81.5 +/- 6.4 vs. 99.3 +/- 5.6 ng/l, P = 0.02).


CONCLUSIONS
Vildagliptin lowers postprandial glucose concentrations by stimulating insulin secretion and suppressing glucagon secretion but not by altered insulin action or glucose effectiveness. A novel observation is that vildagliptin alters alpha-cell responsiveness to insulin administration, but the significance of this action is as yet unclear.
Dalla Man
Chiara
C
Department of Information Engineering, University of Padua, Padua, Italy.
Bock
Gerlies
G
Giesler
Paula D
PD
Serra
Denise B
DB
Ligueros Saylan
Monica
M
Foley
James E
JE
Camilleri
Michael
M
Toffolo
Gianna
G
Cobelli
Claudio
C
Rizza
Robert A
RA
Vella
Adrian
A
D000218:Adamantane / Q000031:analogs & derivatives* / Q000627:therapeutic use; D001786:Blood Glucose / Q000187:drug effects / Q000378:metabolism*; D002096:C-Peptide / Q000097:blood; D018592:Cross-Over Studies; D003924:Diabetes Mellitus, Type 2 / Q000188:drug therapy* / Q000503:physiopathology; D004063:Digestion / Q000187:drug effects / Q000502:physiology*; D054873:Dipeptidyl-Peptidase IV Inhibitors / Q000627:therapeutic use*; D004311:Double-Blind Method; D005934:Glucagon / Q000097:blood / Q000378:metabolism; D006801:Humans; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D007328:Insulin / Q000097:blood / Q000378:metabolism*; D000078790:Insulin Secretion; D009570:Nitriles / Q000627:therapeutic use*; D010919:Placebos; D019518:Postprandial Period / Q000187:drug effects / Q000502:physiology; D011759:Pyrrolidines / Q000627:therapeutic use*; D012528:Satiety Response / Q000187:drug effects; D000077597:Vildagliptin
D001786:Blood Glucose; D002096:C-Peptide; D054873:Dipeptidyl-Peptidase IV Inhibitors; D007004:Hypoglycemic Agents; D007328:Insulin; D009570:Nitriles; D010919:Placebos; D011759:Pyrrolidines; D005934:Glucagon; D000077597:Vildagliptin; D000218:Adamantane